BIOORGANIC CHEMISTRY
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2022
·
IF 5.307
Chuansheng Yao,Xiaoying Jiang,Rui Zhao,Zhichao Zhong,Jiamin Ge,Junlong Zhu,Xiang-Yang Ye,Yuanyuan Xie,Zhen Liu,Tian Xie,Renren Bai
A series of N -propargylamine-hydroxamic acid/ o -aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and propargylamine were designed and synthesized as HDAC1/MAO-B dual inhibitors for the treatment of Alzheimer’s disease. Most of the hybrids displayed moderate to good MAO-B inhibitory activities. Among them, Hybrid If exhibited the most potent activity against MAO-B and HDAC1 (MAO-B, IC 50 = 99.0 nM; HDAC1, IC 50 = 21.4 nM) and excellent MAO selectively (MAO-A, IC 50 = 9923.0 nM; SI = 100.2). Moreover, compound If significantly reversed Aβ1-42-induced PC12 cell damage and decreased the production of intracellular ROS, exhibiting favorable antioxidant activity. More importantly, hybrid If instantly penetrated the BBB and accumulated in brain tissue as well as markedly ameliorated cognitive dysfunction in a Morris water maze ICR mice model. In summary, HDAC1/MAO-B dual inhibitor If is a promising potential agent for the therapy of Alzheimer’s disease.
研究领域:
神经生物学
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药物化学
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医学
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Hai-Tao Yang,Guan Wang,Peng-Cheng Zhu,Zhao-Yang Xiao
Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation , and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro . EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo . In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.
研究领域:
心血管疾病
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分子生物学
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药理学
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细胞生物学
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PubMed
高影响因子
Marine Drugs
·
2024
·Vol. 22
·期 6
·250
·
IF 4.9
Wanting Hao,Leyan Wang,Tongqiang Xu,Geng Jia,Yuqi Jiang,Chong Qin,Xiaoyang Li
Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound25cexhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover,25cexhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of25cas a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.
研究领域:
肿瘤学
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药理学
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血液学
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DOI
高影响因子
Food & Function
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2024
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IF 5.1
Li Fan,Lijuan Zhao,Yangbo Zhu,Lin Li,Xueping Yang,Ping Ma,Jian Liu,Qingwei Zhao,Xiaobo Li
Hydroxytyrosol (HT), a phenolic extra–virgin olive oil compound used as a food supplement, has been recognized to protect liver function and alleviate stress–induced depressive–like behaviors. However, its protective effects against stress–induced liver injury (SLI) remain unknown. Here, the anti–SLI effect of HT was evaluated in mice with chronic unpredictable mild stress–induced SLI. Network pharmacology combined with molecular docking was used to clarify the underlying mechanism of action of HT against SLI, followed by experimental verification. The results showed that accompanying with the alleviation of HT on stress–induced depressive–like behaviors, HT was confirmed to exert the protective effects against SLI, as represented by reduced serum corticosterone (CORT), aspartate aminotransferase and alanine aminotransferase activities, as well as repair of liver structure, inhibition of oxidative homeostasis collapse, and inflammation reaction in the liver. Furthermore, core genes including histone deacetylase 1 and 2 (HDAC1/2), were identified as potential targets of HT in SLI based on bioinformatic screening and simulation. Consistently, HT significantly inhibited HDAC1/2 expression to maintain mitochondrial dysfunction in an autophagy–dependent manner, which was confirmed in a CORT–induced AML–12 cell injury and SLI mice models combined with small molecule inhibitors. We provide the first evidence that HT inhibits HDAC1/2 to induce autophagy in hepatocytes for maintaining mitochondrial dysfunction, thus preventing inflammation and oxidative stress for exerting an anti‒SLI effect. This constitutes a novel therapeutic modality to synchronously prevent stress‒induced depression‒like behaviors and liver injury, supporting the advantaged therapeutic potential of HT.
研究领域:
药理学
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分子生物学
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神经科学
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肝病学
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DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 9
·
IF 7.7
Chunbo Zhang,Lin Liu,Yong Huang,Zibing Liao,Chuan He,Gaoshan Xu,Jiabing Zhu,Xiaopeng Yuan,Jin Su,Chao Gao,Yuanyuan Zhang,Benben Huang,Miao Cao,Weijian Zhu,Jin Liu,Liwen Zhao,Yipan Lai,Xiurong Gao,Linlin Liu,Xianfa Liu,Jinfang Zhang,Huiqiang Lu,Jianing Zhong
Diabetic complications, including retinopathy, are driven by hyperglycemic metabolic reprogramming and aberrant angiogenic transcription. Recent work highlights lactate accumulation and protein lactylation as key regulators, yet their underlying mechanisms in diabetic retinopathy remain unknown. Here, we report that hyperglycemia triggers aminoacyl-tRNA synthetase 1 (AARS1)-mediated lactylation of histone deacetylase 1 (HDAC1) at lysine 412. This modification sequesters HDAC1 in the cytoplasm, preventing its nuclear translocation and abrogating deacetylation of H3K56. The consequent H3K56ac increase activates transcription of the angiogenic gene vascular endothelial growth factor A (VEGFA). Disruption of the HDAC1 K412 lactylation impairs vascular morphogenesis and causes embryonic lethality in zebrafish, whereas Hdac1-K412A knockin mice are protected from pathological retinal angiogenesis in an STZ-induced diabetic model. Pharmacologically, the small molecule exifone inhibited HDAC1 lactylation, suppressing aberrant angiogenesis in diabetic mice and impairing vascular development in chick embryos. Our findings establish HDAC1 lactylation as a critical metabolic-epigenetic switch and a promising therapeutic target.
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高影响因子
Nano Select
·
2020
·Vol. 2
·期 2
·303-312
·
IF 0
Xin Tian,Yue Lang,Dexuan Gao,Xiang-Xiang Zhang,Hai-Yue Dong,Meng-Meng Gu,Lan Yu,Zeng-Fu Shang
Targeted anti-cancer therapy selectively inhibits the growth of malignant cells by interfering with cancer-specific signaling pathways, and inflicts minimal toxicity to normal tissues. Here, the current study demonstrates black phosphorus quantum dots (BPQDs) can target histone deacetylase 1 (HDAC1), which is overexpressed in multiple tumors and involved in cancer progression. The BPQDs inhibit HDAC1 activity and impair HDAC1-mediated deacetylation of the mitotic spindle protein Eg5 in human renal cell carcinoma (RCC) cells, thereby disrupting the mitotic spindle structure and stalling cell cycle progression. Since HDAC1 regulates multiple aspects of cancer progression, BPQDs can neutralize the malignant potential of cancer cells by suppressing their proliferation and migration, and inducing apoptosis. Further in vitro assays demonstrate BPQDs significantly increase the sensitivity of RCC cells to the clinical chemotherapeutic agent, paclitaxel (PTX). Moreover, animal experiments also indicate the combined approach with both BPQDs and PTX displays better efficacy than PTX alone. These findings demonstrate that BPQDs have potential applications in targeted anti-cancer therapy and can be more effectively treated with chemotherapy.
研究领域:
肿瘤学
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生物医学
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药理学
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DOI
CHEMICO-BIOLOGICAL INTERACTIONS
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2026
·
IF 5.2
Xinrui Yan,Linfeng Ma,Jing Ren,Binyan Chen,Wenxuan Song,Yu Dong,Xiaojiao Li,Yingjie Guo
Valproic acid (VPA), a widely used antiepileptic drug, often induces hepatic steatosis during long-term treatment, though the underlying mechanisms remain incompletely understood. In our study, epileptic patients with abnormal liver function exhibited significantly elevated levels of homocysteine (Hcy) and glutamate (Glu) compared to those with normal liver function. Moreover, Hcy and Glu levels were positively correlated with markers of lipid accumulation and oxidative stress. Similar elevations in Hcy and Glu were observed in VPA-treated mice and hepatocyte models (HepG2, AML12), suggesting that disrupted Hcy/Glu homeostasis may be a hallmark of VPA-induced hepatic steatosis. Further in vitro experiments demonstrated that treatment with either Hcy or Glu not only increased lipid accumulation but also triggered ferroptosis, as indicated by Fe 2+ overload, suppression of the GSH-GPX4 axis, and ACSL4-mediated lipid peroxidation. These effects were attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1), confirming the contribution of ferroptosis to Hcy/Glu-induced hepatotoxicity. Additional investigations revealed that VPA promotes Hcy accumulation by downregulating its catabolic enzymes (MTR, CBS, CTH), while enhancing Glu accumulation through upregulation of its synthetic enzymes (ALDH4A1, GLS) and repression of the catabolic enzyme GLUL, both in vivo and in vitro . The alterations in MTR, CBS, ALDH4A1, and GLS levels were shown to depend on HDAC1, as demonstrated using HDAC1 knockdown and overexpression systems in HepG2 cells. In summary, VPA disrupts Hcy/Glu homeostasis via HDAC1, leading to ferroptosis and subsequent hepatic steatosis. These findings highlight the HDAC1-Hcy/Glu-ferroptosis axis as a promising therapeutic target for mitigating VPA-induced hepatotoxicity.
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PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2025
·Vol. 48
·期 12
·1897-1905
·
IF 1.7
Xiaojun Zhang,Fang Wang,Yuna Dai,Zhaoyu Gao,Jianchao He
Platycodon grandiflorum (P. grandiflorum), a traditional Chinese herbal medicine, possesses various biological activities. Among its constituents, polygalacin D (PGD) stands out as one of the principal compounds. This study determined the regulatory effect of PGD on breast cancer progression. Breast cancer cells MCF-7 and BT474 were treated with different concentrations of PGD. Colony formation assays, the detection of Ki67 expression, and cell cycle analysis were performed to verify the effect of PGD on the proliferation of breast cancer cells. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, flow cytometry, and examination of caspase-3 activity were conducted to assess the changes in apoptosis following PGD treatment. In addition, the co-treatment of PGD and cisplatin (DDP) on cells was performed to explore the effect of PGD on the chemosensitivity of DDP. Furthermore, bioinformation analysis suggested that histone deacetylase 1 (HDAC1) and HDAC2 were the downstream factors of PGD, and the effect of PGD on their expression was assessed. PGD inhibited breast cancer cell proliferation, as evidenced by reduced colony formation, downregulation of Ki67 expression, and induction of cell cycle arrest. Additionally, PGD treatment significantly increased caspase-3 activity and elevated the rate of cell apoptosis and TUNEL-positive cells. Furthermore, PGD was found to enhance the chemosensitivity to DDP. Mechanistically, PGD reduced the expression of HDAC1 and HDAC2 by promoting their protein degradation. Cell proliferation induced by HDAC1 or HDAC2 was also overcome by PGD. In conclusion, PGD was confirmed as an effective tumor inhibitor that suppressed the development of breast cancer by regulating HDAC1 and HDAC2.
研究领域:
肿瘤学
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分子生物学
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药理学
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天然产物化学
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表观遗传学
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PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Xiaomei Shi,Jiangbo Liang,Zhuoyan Wu,Mengjiao She,Yan Liu,Chunguang Zhu,Ling Fang,Ranxi Dong,Qiong Wu,Wenjie Mei
Glioblastoma, the most prevalent and highly aggressive primary brain tumor, is characterized by high clinical recurrence rates and significant resistance to conventional therapies, highlighting the need for innovative targeted agents to address current treatment limitations. This study employed an integrated computational and experimental strategy to identify novel iodo-phenanthroimidazole derivatives (compounds 1–3 ). Compound 3 was identified as a lead candidate that inhibits HDAC1 and may trigger autophagy, thereby suppressing glioblastoma progression. Molecular docking and molecular dynamics simulations indicated stable interactions between compound 3 and the HDAC1 catalytic site (estimated binding energies of −7.75 and − 7.74 kcal/mol), with a notable halogen bond between the iodine atom and Asp104. The phenanthroimidazole scaffold was proposed as a potential zinc-binding group (ZBG) for HDAC1 inhibition. Biophysical validation using isothermal titration calorimetry (ITC) confirmed submicromolar binding affinity ( K d = 1.04 × 10 −7 M, Δ H = −91.24 kJ·mol −1 ). In vitro evaluation demonstrated potent inhibition of U87-MG glioblastoma cell proliferation (IC 50 = 0.23 μM), and flow cytometric analysis indicated concomitant cell cycle arrest at both G2/M and S phases. Transmission electron microscopy revealed autophagic vacuoles containing damaged mitochondria, and immunofluorescence showed an increased LC3-II/LC3-I ratio. Together with the observed loss of mitochondrial membrane potential and ATP depletion, these findings are consistent with the induction of a mitophagy-like process. Using an in vivo zebrafish orthotopic glioblastoma model, the lead compound demonstrated blood–brain barrier penetration and effectively suppressed tumor growth and U87-MG cell metastasis. This work highlights the potential of iodo-phenanthroimidazole derivatives as a novel therapeutic strategy for glioblastoma. The data support a model in which HDAC1 inhibition is associated with mitochondrial dysfunction and mitophagy, contributing to tumor suppression.
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Xinyu Qian,Lin Zhu,Mengzhen Xu,Haoli Liu,Xinyan Yu,Qiuyue Shao,Jing Qin
Small cell lung cancer (SCLC) is a subtype of lung cancer with a very poor overall survival rate due to its extremely high proliferation and metastasis predilection. Shikonin is an active ingredient extracted from the roots of Lithospermum erythrorhizon, and exerts multiple anti-tumor functions in many cancers. In the present study, the role and underlying mechanism of shikonin in SCLC were investigated for the first time. We found that shikonin effectively suppressed cell proliferation , apoptosis , migration, invasion, and colony formation and slightly induced apoptosis in SCLC cells. Further experiment indicated the shikonin could also induced ferroptosis in SCLC cells. Shikonin treatment effectively suppressed the activation of ERK, the expression of ferroptosis inhibitor GPX4 , and elevated the level of 4-HNE, a biomarker of ferroptosis. Both total ROS and lipid ROS were increased, while the GSH levels were decreased in SCLC cells after shikonin treatment. More importantly, our data identified that the function of shikonin was dependent on the up-regulation of ATF3 by performing rescue experiments using shRNA to silence the expression of ATF3, especially in the total and lipid ROS accumulaiton. Xenograft model was established using SBC-2 cells, and the results revealed that shikonin also significantly inhibited tumor growth by inducing ferroptosis. Finally, our data further confirmed that shikonin activated ATF3 transcription by impairing the recruitment of HDAC1 mediated by c-myc on the ATF3 promoter , and subsequently elevating of histone acetylation . Our data documented that shikonin suppressed SCLC by inducing ferroptosis in a ATF3-dependent manner. Shikonin upregulated the expression of ATF3 expression via promoting the histone acetylation by inhibiting c-myc-mediated HDAC1 binding on ATF3 promoter.
研究领域:
肿瘤学
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分子生物学
·
细胞生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2019
·
IF 5.808
Yahui Huang,Shuqiang Chen,Shanchao Wu,Guoqiang Dong,Chunquan Sheng
A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o .) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.
研究领域:
药理学
·
肿瘤学
·
药物化学
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DOI
PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2023
·
IF 5.6
Ze Wang,Li Zhao,Bo Zhang,Jiahe Feng,Yule Wang,Bin Zhang,Haixiao Jin,Lijian Ding,Ning Wang,Shan He
Pan-histone deacetylase (HDAC) inhibitors often have some toxic side effects. In this study, three series of novel polysubstituted N-alkyl acridone analogous were designed and synthesised as HDAC isoform-selective inhibitors. Among them, 11b and 11c exhibited selective inhibition of HDAC1, HDAC3, and HDAC10, with IC50 values ranging from 87 nM to 418 nM. However, these compounds showed no inhibitory effect against HDAC6 and HDAC8. Moreover, 11b and 11c displayed potent antiproliferative activity against leukaemia HL-60 cells and colon cancer HCT-116 cells, with IC50 values ranging from 0.56 μM to 4.21 μM. Molecular docking and energy scoring functions further analysed the differences in the binding modes of 11c with HDAC1/6. In vitro anticancer studies revealed that the hit compounds 11b and 11c effectively induced histone H3 acetylation, S-phase cell cycle arrest, and apoptosis in HL-60 cells in a concentration-dependent manner.
研究领域:
药理学
·
肿瘤学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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